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Ann Surg. 2005 September; 242(3): 375–383. doi: 10.1097/01.sla.0000179622.37270.36. | PMCID: PMC1357745 |
Copyright © 2005 Lippincott Williams & Wilkins, Inc. A Comprehensive Evaluation of Perioperative Adjuncts During Minimally Invasive Parathyroidectomy Which Is Most Reliable? Herbert Chen, MD, FACS, Eberhard Mack, MD, FACS, and James R. Starling, MD, FACS From the Section of Endocrine Surgery, Department of Surgery, The University of Wisconsin Medical School, Madison, Wisconsin.
Objective: To determine the utility of several perioperative adjuncts for parathyroid localization during parathyroid surgery, we prospectively compared the accuracy of sestamibi–single photon emission computed tomography (SPECT) scanning, radioguided surgery, and intraoperative parathyroid hormone (ioPTH) testing. Summary and Background Data: Minimally invasive parathyroidectomy (MIP) is rapidly becoming the procedure of choice in patients with primary hyperparathyroidism (HPT). Several perioperative adjuncts can be used to localize parathyroid adenomas, including sestamibi-SPECT scanning, radioguided surgery, and ioPTH testing. However, the relative value of each of these technologies is unclear. Methods: Between March 2001 through September 2004, 254 patients with primary HPT underwent parathyroidectomy. All patients had preoperative imaging studies and underwent radioguided surgery with a gamma probe and ioPTH testing. The use of each perioperative adjunct was determined based on the intraoperative findings. Results: The mean age of patients was 61 ± 1 year. The mean calcium and parathyroid hormone levels were 11.4 ± 0.1 mg/dL and 136 ± 6 pg/mL, respectively. Of the 254 patients, 206 (81%) had a single parathyroid adenoma, 28 (11%) had double adenomas, 19 (8%) had hyperplasia, and one had parathyroid cancer. All resected parathyroid glands were hypercellular (mean weight = 895 ± 86 mg). The cure rate after parathyroidectomy was 98%. The positive predictive values for sestamibi scanning, radioguided surgery, and ioPTH testing were 81%, 88%, and 99.5%, respectively. Conclusions: This series is one of the largest to date that prospectively compares the use of sestamibi scanning, radioguided surgery, and ioPTH testing. Of all the perioperative adjuncts used during parathyroid surgery, ioPTH testing has the highest sensitivity, positive predictive value, and accuracy. Thus, the inherent variability of sestamibi scanning and radioguided techniques emphasizes the critical role of ioPTH testing during parathyroid surgery. It has often been said that the best localization study for a patient with primary hyperparathyroidism (HPT) is “a good endocrine surgeon.” Based on this philosophy, the standard treatment of primary HPT has been open parathyroidectomy with identification of the 4 parathyroid glands and resection of the abnormally enlarged gland(s). Open parathyroidectomy and 4-gland exploration is associated with a >95% cure rate and minimal morbidity in the hands of an experienced endocrine surgeon. 1–3 However, with the continued improvements in parathyroid imaging techniques, minimally invasive parathyroidectomy is rapidly becoming the procedure of choice in patients with primary HPT. 4–6 In contrast to open parathyroidectomy, in which operative visualization is used to confirm whether or not the other parathyroid glands are hyperplastic, minimally invasive procedures target a single parathyroid gland and depend on modern perioperative adjuncts to determine if any other hyperfunctioning glands are present. Several investigators have shown that minimally invasive parathyroidectomy leads to lower hospital costs, shorter length of stays, a lower incidence of transient hypocalcemia, and equally high cure rates with lower complication rates. 3–5,7Many parathyroid perioperative adjuncts have been described, including Tc-99m sestamibi scanning, 4,8 radioguided surgery, 2,9–12 and intraoperative parathyroid hormone testing. 13–15 Successful minimally invasive parathyroid operations are highly dependent on accurate data obtained from these perioperative adjuncts. Several investigators have reported the benefit of each of these technologies during minimally invasive parathyroidectomy. 14,16,17 However, the relative value of each of these technologies is unclear as a result of the lack of data directly comparing these adjuncts in a large group of patients. Therefore, the purpose of this study was to directly compare the use of Tc-99m-sestamibi scanning, radioguided surgery, and intraoperative PTH testing in a large cohort of patients undergoing surgery for primary HPT. From March 2001 to September 2004, 269 consecutive patients with primary HPT underwent parathyroidectomy by one surgeon (HC) at the University of Wisconsin. Of these 15 patients were not candidate for minimally invasive parathyroidectomy as a result of suspected multiple endocrine neoplasia type I or as a result of the need for standard open surgery for a concomitant procedure such as thyroidectomy. Therefore, the remaining 254 patients were candidates for a minimally invasive approach. All patients had preoperative imaging studies. Our first-line imaging modality is Tc-99m-sestamibi single photon emission computed tomography (SPECT) scanning. Of the 254 patients, 242 underwent sestamibi scanning. The remaining 12 patients had a thallium–technetium substraction scan or cervical ultrasound scan as their initial imaging study that was positive for a single parathyroid adenoma. Thus, these 12 patients did not have an additional sestamibi scan as a result of their other positive scan. The following definitions were used for calculating the sensitivity, positive predictive value, and accuracy of sestamibi scanning. A true-positive was when the scan was read as a single parathyroid adenoma and the operative findings concurred. A true-negative was when the scan revealed multiple enlarged glands or no imaged gland, and there were multiple hyperplastic parathyroid glands found at surgery. A false-positive was when the scan predicted a single parathyroid adenoma, whereas the operative findings revealed multigland disease. A false-negative was when the scan did not localize a parathyroid gland but a single adenoma was found at surgery. In calculating the accuracy of the localizing study, scans were used to preoperatively predict the entity of single gland disease and were not analyzed on the ability of this test to localize which foci to dissect first. We routinely use radioguided techniques for patients undergoing surgery for primary, secondary, and tertiary HPT. 9,11,18 All but 2 patients in this series underwent radioguided surgery with an 11-mm collimated gamma probe. The contraindications for radioguided surgery in the 2 patients were pregnancy and dose limitations. We have previously described our technique for radioguided parathyroidectomy. 2,9 Briefly, patients are injected with 10 mCi of Tc-99m-sestamibi 1 to 2 hours before surgery on average. In the operating room, background counts are obtained by placing an 11-mm collimated gamma probe (Neoprobe 2000; Ethicon Endo-Surgery Breast-Care, Cincinnati, OH) on the thyroid isthmus through the skin. After incision, intraoperative scanning is performed looking for radionuclide counts more than background to localize abnormal parathyroid glands. The counts obtained by scanning on the identified enlarged parathyroid gland in situ were recorded as “in vivo” counts and expressed as a percentage of the background counts. After excision of the enlarged parathyroid, the tissue is placed on top of the gamma probe (directed away from the patient) to determine “ex vivo” counts. Ex vivo counts are expressed as a percentage of background counts. An ex vivo parathyroid count >20% of background is definitive for parathyroid tissue. All 254 patients in this study had intraoperative PTH testing. We have previously described our protocol for intraoperative PTH testing and interpretation at the University of Wisconsin. 19 All PTH levels were analyzed on the Elecsys 2010 machine. For each patient, a PTH level is drawn before surgical incision and serves as the “baseline” level. After resection of the enlarged parathyroid gland, PTH levels are drawn after 5, 10, and 15 minutes. Our criteria for a curative resection is a >50% drop in intraoperative PTH levels compared with baseline at 5, 10, or 15 minutes. If a >50% drop occurs, then the operation is terminated. If the PTH level fails to fall, the neck is explored for a second adenoma or additional hyperplastic glands. After resection of the second adenoma and/or other enlarged parathyroids, the PTH level is checked again after an additional 5 and 10 minutes. All data were recorded prospectively. Surgical cure was defined as a serum calcium level <10.2 mg/dL at least 6 months after surgery. Recurrence was defined as a serum calcium level exceeding 10.2 mg/dL in consecutive samples 6 months after surgery. Persistent disease was defined as a serum calcium level greater than 10.2 mg/dL within 6 months of surgery. Data were recorded as mean ± standard error of mean. Statistical analysis was performed with SPSS software (SPSS Inc.). Statistical significance was defined as a P < 0.05. Patients Data Patient demographic data are shown in Table 1. The median age was 62 years (range, 15–90 years). All had primary HPT as determined by the presence of an elevated preoperative serum calcium (mean = 11.4 ± 0.1 mg/dL) and an inappropriately high intact PTH level (mean = 136 ± 6 pg/mL). In many cases, patients also presented with low serum phosphorus levels. Several patients with severe or longstanding primary HPT also had elevated serum alkaline phosphatase levels. | TABLE 1. Demographic and Laboratory Data |
Operative Findings and Outcomes At the time of surgery, the mean weight of the resected parathyroid glands was 895 ± 86 mg ( Table 2). Of the 254 patients, 206 (81%) had a single adenoma as the cause of their primary HPT. Twenty-eight patients (11%) had double adenomas, whereas 19 (8%) had 3- or 4-gland hyperplasia. One patient (0.5%) had parathyroid carcinoma. The mean postoperative serum calcium and intact PTH levels were 9.3± 0.0 mg/dL and 48 ± 2 pg/mL, respectively. With long-term follow up, 249 patients remained normocalcemic. Four patients had persistent primary HPT. One patient had recurrent primary HPT. This patient initially had a minimally invasive procedure with resection of a 750-mg parathyroid adenoma and remained normocalcemic until 36 months later when calcium of 10.9 mg/dL and an intact PTH level of 238 pg/mL were recorded. This patient underwent another minimally invasive resection of a second adenoma weighing 272 mg and has been normocalcemic for 7 months postoperatively. Therefore, the overall cure rate after parathyroidectomy in this single surgeon series was 98% (249 of 254). Sestamibi Scans To determine the utility of Tc-99m-sestamibi scanning, we compared the intraoperative findings to the preoperative scans. Most patients (n = 242) had sestamibi scanning as their initial imaging study. In 160 of the 242 cases, the parathyroid gland localized by sestamibi scan was the only enlarged parathyroid gland confirmed during surgery (true-positive cases). In 15 patients, the sestamibi scan was negative for a parathyroid adenoma and the patients were found to have either double adenomas or parathyroid hyperplasia (true-negative cases). In 37 cases, the sestamibi scan was falsely positive. That is, although the sestamibi scan suggested that only a single adenoma was the etiology of the patient's primary HPT, the operative findings suggested otherwise. Of these 37 false-positive cases, the true etiology of the HPT was a double adenoma in 15 patients and hyperplasia in 11 patients. In the remaining 11 cases, a contralateral parathyroid adenoma was found. In 30 of the 242 cases, the sestamibi scan was falsely negative. In these 30 patients, although the sestamibi scan was negative, a single adenoma was found at the time of surgery. Radioguided Surgery At the time of radioguided surgery, the mean background counts from the thyroid isthmus were 226 ± 7, whereas the counts from the mean in vivo enlarged parathyroid gland were 347 ± 12. The mean ex vivo counts from the resected parathyroid gland were 175 ± 11. All abnormal parathyroid glands had ex vivo counts that exceeded 20% of the background. The utility of the gamma probe during parathyroidectomy was also studied. In 208 of the 252 cases in which radioguided resection was used, the gamma probe successfully localized a single parathyroid gland as the etiology of the patient's primary HPT (true-positive cases). In one patient, after resection of one parathyroid adenoma, the gamma probe suggested that a second adenoma was present. Further exploration revealed a second adenoma. This represented the only true-negative case. In 27 cases, the gamma probe was falsely positive. Although the gamma probe suggested that only a single adenoma was the etiology of the patient's primary HPT, the operative findings differed. Of these 27 false-positive cases, the true etiology of the HPT was a double adenoma in 12 patients and hyperplasia in 13 patients. In the remaining 2 cases, a contralateral parathyroid adenoma was found. In 16 of the 252 cases, the gamma probe was falsely negative. Intraoperative Parathyroid Hormone Testing All 254 patients had intraoperative PTH testing. In 222 cases, after resection of a single parathyroid adenoma, the intraoperative PTH level fell by >50% indicating resection of all hyperfunctioning tissue. All of these 222 patients were cured, representing the true-positive cases. Importantly, in 28 patients, the intraoperative PTH level did not fall by 50% prompting additional exploration to look for other hyperfunctioning parathyroid glands. In these 28 cases, other enlarged parathyroid glands were present (true-negative cases). There was only one false-positive case. This patient had resection of a 750-mg parathyroid adenoma. The intraoperative PTH levels started at 237 pg/mL and fell to 218, 137, and 118 pg/mL at 5, 10, and 15 minutes after resection. Thus, this patient had a greater than 50% fall in intraoperative PTH levels. This patient remained normocalcemic for 36 months. At 36 months after surgery, calcium of 10.9 mg/dL and an intact PTH level of 238 pg/mL were recorded. This patient subsequently underwent another minimally invasive resection of a second adenoma weighing 272 mg and has been normocalcemic for 7 months postoperatively. There were only 3 false-negative cases. In each of these cases, the patient underwent resection of a single parathyroid adenoma and the intraoperative PTH level did not fall, prompting further exploration. In the first of the 3 false-negative cases, an intrathyroidal parathyroid adenoma was resected and the intraoperative PTH fell from 72 to 40 pg/mL. In the second case, a 131-mg parathyroid gland was removed and the intraoperative PTH started at 44 and dropped to 30 pg/mL. In the third case, the intraoperative PTH fell from 86 to 47 pg/mL after resection of a single adenoma. A bilateral exploration was performed in each of these cases. No other hyperfunctioning tissue was found, but the patients have normal calcium and PTH levels to date, indicating that the intraoperative assay was falsely negative. Comparison of the Parathyroid Adjuncts In comparing sestamibi scanning, radioguided surgery with the gamma probe, and intraoperative PTH testing, all had high sensitivities (), positive predictive values (), and accuracies (). However, intraoperative PTH testing was superior to the other 2 techniques in all 3 categories. Impressively, the positive predictive value of intraoperative PTH testing was >99%. Minimally invasive parathyroidectomy has revolutionized the approach to patients with primary HPT. At many of the large endocrine surgery centers, minimally invasive parathyroidectomy has replaced bilateral neck exploration as the operation of choice for most patients with primary HPT. In contrast to bilateral neck exploration, in which operative visualization is used to confirm whether or not the other parathyroid glands are hyperplastic, minimally invasive procedures target a single parathyroid gland and depend on modern perioperative adjuncts to determine if any other hyperfunctioning glands are present. Several centers have reported that that minimally invasive parathyroidectomy leads to lower hospital costs, shorter length of stays, a lower incidence of transient hypocalcemia, and equally high cure rates with lower complication rates. 3–5,7The success of minimally invasive parathyroidectomy is highly dependent on accurate imaging and other adjuncts that can predict the presence of single gland disease. Ideally, because approximately 80% of patients have a single adenoma as the etiology of their primary HPT, most patients should be candidates for a targeted approach. However, given the limitations of parathyroid localization tests, it is often a balance between sensitivity and specificity. How can we offer this less invasive procedure to the maximum number of patients while maintaining the high cure rates associated with parathyroidectomy? There are many different approaches to this dilemma using a variety of technologies. In this study, we attempted to determine which particular adjunct was most useful during minimally invasive parathyroidectomy. Tc-99m sestamibi-SPECT scanning has been shown to be the best imaging modality to localize parathyroid adenomas. 3 However, it is not perfect. Most large series report sensitivities in the 70% to 90% range. In this study, sestamibi scanning had an 84% sensitivity, an 81% positive predictive value, and an 72% accuracy. There were 30 false-negatives and 37 false-positives. We and others have shown that many of the false-negative scans are as a result of small (<200-mg) parathyroid adenomas. 20 Of the 37 false-positive cases, 11 patients (30%) had a contralateral parathyroid adenoma, whereas 26 (70%) had multigland disease. Radioguided surgery is perhaps the most controversial of all the parathyroid adjuncts. Many endocrine surgeons have reported that radioguided techniques rarely provide any additional information over the sestamibi scan itself and should not be routinely used during parathyroid operations. 21,22 However, others have shown that radioguided parathyroidectomy is feasible and offers several advantages to nonradioguided surgery. 7,11,17 In this study, the gamma probe had a 93% sensitivity, an 88% positive predictive value, and an 83% accuracy, all of which were higher when compared with sestamibi scanning. There were lower numbers of false-positive and false-negative cases. Specifically, the use of the gamma probe reduced the number of false-positives as a result of contralateral adenomas (from 30% to 10%) compared with sestamibi. Although improving on overall accuracy, we have found the gamma probe to be extremely useful in localizing the enlarged parathyroid(s) intraoperatively, especially in ectopic sites. 10,12 Furthermore, we have recently shown that radioguided techniques may shorten operative times. 11 Thus, we routinely use the gamma probe for almost all patients undergoing parathyroidectomy for primary, secondary, and tertiary HPT. Lastly, in this study, intraoperative PTH testing had an 99% sensitivity, an 99.6% positive predictive value, and an 98% accuracy. In fact, the only false-negative case was a patient who had a >50% drop in intraoperative PTH values and was normocalcemic for 36 months postoperatively. She then recurred and therefore was included as a false-positive case. However, because she was normocalcemic for over 36 months postoperatively, many would not consider this a failure of intraoperative PTH testing. Thus, the intraoperative PTH assay was 100% in predicting immediate operative cure. There were only 3 false-negative cases. In these 3 patients, the intraoperative PTH values did not fall by >50% after curative surgery. These patients were subject to unnecessary bilateral neck exploration. The reason for the inadequate drop in intraoperative PTH levels could be the result of the fact that all 3 patients were elderly and had slightly elevated creatinine levels. Thus, the half-life of PTH may have been greater than the 3 to 4 minutes seen in the majority of patients. The use of intraoperative PTH testing for parathyroid surgery has been questioned by some investigators. Sebag and colleagues have shown that intraoperative PTH testing did not improve the outcomes of patients undergoing parathyroidectomy at their institution. 23 Haciyanli and associates have also found that intraoperative PTH testing does not reliably predict double adenomas. 24 The Mayo Clinic group has recently argued that minimally invasive parathyroidectomy can be performed successfully without the intraoperative PTH assay. 25 However, despite these reports, we and other have clearly shown that intraoperative PTH testing leads to higher cure rates in patients undergoing parathyroidectomy for primary HPT. 14,19 Furthermore, it is the most accurate predictor of multigland disease. 26 As demonstrated in this study, intraoperative PTH testing was the most reliable adjunct during parathyroidectomy. In conclusion, this series is one of the largest to date, which prospectively compares the use of sestamibi scanning, radioguided surgery, and intraoperative PTH testing. Of all the perioperative adjuncts used during parathyroid surgery, intraoperative PTH testing had the highest sensitivity, positive predictive value, and accuracy. Thus, the inherent variability of sestamibi scanning and radioguided techniques emphasizes the critical role of ioPTH testing during parathyroid surgery. Discussions Dr. George L. Irvin, III (Miami, Florida): For those of us who take care of patients with primary hyperparathyroidism, this study by Dr. Herbert Chen and the group from Wisconsin is an important one. We have seen a marked change in the operative approach in these patients, from the traditional bilateral neck exploration with the excision of all enlarged parathyroid glands based on the surgeon's judgment, to a limited or targeted excision of a localized, hypersecreting gland or glands. Success in returning the patient to postoperative eucalcemia with a minimal neck exploration, that is, without visualizing the remaining parathyroid glands, which may or may not be grossly enlarged, is dependent on hormone dynamics measured by a rapid PTH assay. This assay confirms that all hypersecreting tissue has been excised, or if multiple glands are involved, it signals that further exploration and excision is necessary. The use of this surgical adjunct, the intraoperative PTH assay, which was primarily fashioned to prevent overlooking multiple parathyroid gland involvement has developed, along with several preoperative localization techniques, into the so-called minimally invasive parathyroidectomy with advantages noted by Dr. Chen. With the wide acceptance of the Tc-99m-sestamibi nuclear scanning technique for preoperative localization, some surgical leaders have questioned the need for intraoperative PTH assays. These surgeons would base their operative approach on the scan imaging alone. The present study points clearly to the inadequacies of this localization method. Our own studies confirm the data presented today and show that although MIBI scans correctly identified 81% of all hypersecreting parathyroid glands, 19% were either completely negative or incorrect localization foci at parathyroidectomy. Without the quantitative hormone assay to confirm successful excision of all abnormal tissue, minimally invasive parathyroidectomy based solely on MIBI localization will have unacceptable high failure rate. The newest improvement in localization of abnormal parathyroid glands is cervical ultrasound by the surgeon. This technique performed in real-time by the surgeon as a 5–10 minute exam in the outpatient clinic is as accurate as the MIBI scan alone. What's more important is that this simple, easy to use modality has improved the localization accuracy of our MIBI scans by 10%. Dr. Chen, has your group looked into ultrasonography by the surgeon as a way to improve localization of abnormal parathyroid glands? If so, how does this quick and less expensive technique compare with the modalities reported today? Dr. Herbert Chen (Madison, Wisconsin): Thank you, Dr. Irvin, for your comments. Certainly we all must recognize the seminal contribution you have made in the development of intraoperative PTH testing convincing many people in the audience that this was the way to go, and certainly all of us have learned from you and have implemented that into our practice. That gets to my answer to your first question. Certainly we learned all that from you. And I could probably learn how to use ultrasound from you again, since I do not routinely use that. And I agree that data from your institution as well as others have shown that this is another tool that can definitely help us in the OR. But I think that this data and your data with intraoperative PTH testing shows that it is really the critical test that we need during parathyroid surgery. You alluded to the inexpensive cost of ultrasound. And I will just point out that PTH testing can also be inexpensive if you use automated machines. Dr. Orlo H. Clark (San Francisco, California): Drs. Chen, Starling and Mack are to be congratulated for their 98% cure rate of 254 patients with sporadic primary hyperparathyroidism not requiring thyroid operations. Their results with sestamibi scanning, radioguided surgery, and intraoperative PTH are also excellent. The purpose of their investigation was to determine the accuracy of sestamibi-SPECT scanning, radioguided or directed parathyroidectomy, and intraoperative PTH testing. They report that 206 of their 254 patients had a single adenoma, 11% a double adenoma, 8% hyperplasia, and 1 cancer. This observation suggests that the authors did a bilateral approach in these patients and identified all parathyroid glands rather than a focused or scan-directed approach. The approach used for parathyroid operations is important because we, as well as others, have documented that more histologically abnormal parathyroid glands are identified when a bilateral rather than a focused approach is used. However, most of the patients in both groups remain normocalcemic at least for several years. My first question to the authors is to ask what operative approach did they use and following this investigation, have they changed their surgical approach for these patients when the parathyroid tumor is identified preoperatively? As the authors have observed about 80–85% of patients with primary sporadic hyperparathyroidism have only 1 abnormal parathyroid tumor. The cure rate is high in these patients and the recurrence rate is very low. Although preoperative localization tests are not necessary when a bilateral approach is planned, such studies as sestamibi scanning with or without SPECT can not only identify the parathyroid tumor, but perhaps more importantly can also identify parathyroid tumors in ectopic sites such as a mediastinal, undescended, or intrythyroid parathyroid gland. The accuracy of sestamibi scanning, other localization tests, and intraoperative PTH testing, unfortunately, is not as accurate when they are needed most, that is in patients with multiple abnormal parathyroid glands, as you have just reported. The authors’ success rate of 81% for sestamibi scanning is what is generally reported for patients having a bilateral approach. When one uses a focused approach the success rate is up to 90% or higher because the surgeon is only moving 1 parathyroid gland, and the operation is directed by the preoperative localizing studies. An experienced nuclear physician medicine is obviously necessary, like an experienced ultrasonographer, for the best results. My second question is somewhat related to Dr. Irvin's question: How many of your patients with sestamibi failures had multiple abnormal parathyroid glands and would you recommend an ultrasound exaination for patients who had a negative sestamibi scan or in patients who the sestamibi scan suggests there is more than one abnormal parathyroid tumor? Also, how helpful overall was SPECT? We find that it is especially helpful for identifying parathyroid tumors in the anterior and posterior mediastinum, but how expensive was it for your group of patients? The authors report a positive predictive value of 88% for radioguided surgery. We, as well as others, have previously prospectively investigated the accuracy of this technique and did not find it to be any more helpful than the preoperative sestamibi scan. If you can see the parathyroid tumor preoperatively, and if you know how to do the parathyroid surgery, why do you need to repeat the sestamibi scan in the operating room? My next question is, therefore, whether the surgeons were aware of the position of the parathyroid gland by your preoperative sestamibi scan prior to using the probe intraoperatively? If so, it is not really useful to compare the accuracy of preintraoperative localization. Unfortunately, you cannot compare these 2 procedures in the opposite way. Also, since this information most likely was available and these localization procedures were done sequentially, was the probe helpful at all in patients with mediastinal tumors or in patients with negative preoperative sestamibi scans? I think you had 1 patient in whom it helped. Thus, it is difficult to know whether the 88% success rate with the probe is really better than preoperative sestamibi scanning alone. The authors report that intraoperative PTH testing had the highest positive predictive value of 99.5%. I compliment them on this achievement. I am somewhat surprised, however, about their superb results and how can it be better than the 98% success rate of their operations? It is hard to have a localizing study better than the operative results. I think I know the reason, but I remain somewhat confused. We have found, as have others, that it is necessary to do 2 preoperative intraoperative PTH determinations, 1 after the patient is anesthetized and another immediately prior to removal of the parathyroid tumor. The reason for this is that with manipulation of the parathyroid tumor the PTH level sometimes increases dramatically and in other patients it sometimes falls more than 50% prior to tumor removal. In fact, in our initial studies we found in about 30% of our patients the PTH didn't fall appropriately at 10 minutes so we went on to further operations and repeated the intraoperative PTH test. My question is: Would you repeat the PTH a fourth time if it didn't fall or at 15 minutes after removal of the parathyroid tumor would you just reoperate on that patient? Dr. Herbert Chen (Madison, Wisconsin): You asked what our approach is. If we see a patient with primary hyperparathyroidism we get a sestamibi scan. If it is positive, which occurs in about 70–80%, we will do a minimally invasive procedure. So the other patients that are sestamibi negative, we will either offer them a bilateral exploration or we will say that we can do another imaging test such as ultrasound, or scan your neck with a gamma probe. We have found about 10% of those patients can have a minimally invasive procedure based on a second imaging study or the use of the gamma probe. Now, of the patients who undergo the minimally invasive procedure, about 90% of those patients will have a single adenoma, 10% will have multiple gland disease. And that is where the intraoperative PTH becomes helpful because then we know at the time of surgery we need to convert those 10% of patients to a bilateral exploration. You asked about the expense of a SPECT scan. We estimate that to be two hundred dollars. I think it adds potentially more localizing information than a plain view because you can tell the depth and you can tell when something is retroesophageal. We have found that the gamma probe is particularly useful in detecting ectopic sites. We have reported a series of 4 patients with mediastinal parathyroids who had video-assisted thoracoscopic surgery with the gamma probe. We have also reported its use up high for very undescended parathyroid glands. I will admit to you that I found the probe very useful when I started. I probably find it less useful now. I would probably say that I don't need the probe in the vast majority of cases. But if you ask the residents, they find the probe very useful. You asked about when I draw PTH levels. We don't draw preincision levels because we get that 15-minute level and therefore if the level is artificially elevated at 5 minutes, our 10- and 15-minute samples serve as our 5- and 10-minute samples. Dr. Richard A. Prinz (Chicago, Illinois): Dr. Chen, let me compliment you on your excellent work. I question, though, whether you are actually comparing apples and oranges. I think the 3 tests or studies have very different roles or purposes when doing a minimally invasive parathyroidectomy. The sestamibi scan along with ultrasound tells us if it is a potentially possible approach to do, the probe has some purported advantages in the technical aspects of the operation, and the intraoperative parathyroid hormone monitoring tells us if we have completed the operation and can expect a successful outcome. I would like your thoughts on that. You had 4 patients with persistent hyperparathyroidism in this series in addition to 1 with recurrent hyperparathyroidism, but you didn't include all of them in the false positives. Why not? It would seem to me those 5 patients are extremely important, because I would want to know what their levels of intraoperative PTH were and how you were led astray by them. Dr. Herbert Chen (Madison, Wisconsin): Thank you, Dr. Prinz. You are right that we are comparing apples and oranges. One of the reasons I wanted to compare them head to head is because whenever we presented our radioguided data at any meeting, people said, “Well, you use all these different toys: you use sestamibi, you use the radioguided probe, you use intraoperative PTH. Why do you need all these bells and whistles?” And I wanted to try to figure out the relative contribution of each one. Now having said that, your observations are correct that we use sestamibi scanning mostly to determine if a paatient is a candidate for minimally invasive surgery, the probe to help us exactly find the location, and the PTH assay to determine cure. But what I wanted to assess is the reliability of each one, and clearly PTH has the best reliability. We did have those failures. I did not include those failures in the analysis, which I probably should have. Because in each of those cases the PTH assay predicted that I did not cure these patients. So they weren't really false positive or false negative, they were true negatives. And unfortunately, of those 4 patients none of them have come back for another surgery. I have not been able to localize the parathyroid with subsequent imaging so I don't know where they are to show if the sestamibi was wrong or the gamma probe was wrong. Dr. Francis D. Moore, Jr. (Boston, Massachusetts): Thank you for a great series. The failures are important to think about, even though they are few. A number of us who have been doing limited surgeries are starting to accumulate late failures which clearly are double adenomas that the intraoperative PTH testing failed to recognize. What do you do with the patient with a flagrantly positive sestamibi scan? How should that patient really be handled? The positive predictive value of scanning that you report is around 90%. Then you are confronted after taking the adenoma out with about 10 minutes to kill before you get the next blood sample. I imagine I am not the only surgeon who started to use that 10 minutes to see if the other parathyroid on that side can be found. Let's say that other parathyroid is found, and it is very, very small. There is no chance at all, then, that the patient has diffuse hyperplasia. At that point, you have eliminated that 6% of patients out of the pool of 12% with multi-glandular disease. You have also eliminated 1 of the 3 potential locations for double adenoma. So now you are probably down to, in those particular cases, a 2% or so probability that there is a second adenoma. Can you really use any test to rule out a 2% probability? No matter how good the PTH is, is it good enough to assure you that you are accurate at that 2% level? Dr. Herbert Chen (Madison, Wisconsin): I think the data here speaks for itself. We have long-term follow-up on a lot of patients who underwent the minimally invasive procedure. And if you look at Dr. Irvin's data, too, with long-term follow-up, the assay really does predict patients who are going to be normocalcemic postoperatively for at least 6 months, perhaps longer. And we have 1 failure in this case, the 1 recurrence that occurred at 36 months which I scored as a failure of the assay but one could question, well, was that really a failure of the assay? Because we were measuring what is hyperfunctioning at the time, not what is going to happen 36 months from now. And asking about how you can possibly reduce the waiting time or what you do when you have a patient with a flagrantly positive scan, I think there are degrees of positive scans. Some people advocate getting multiple images up front to really assure yourself that is one gland and not using PTH testing. And you can do that, and your cure rate will probably be about 95%. We like to try open up the procedure to as many people as possible, so we will try a minimally invasive procedure on just the hint of a positive localization study knowing that the PTH assay will back us up. We check it at 5 minutes. And I wait for the level before I leave the operating room. 1. Chen H, Zeiger MA, Gordon TA, et al. Parathyroidectomy in Maryland: effects of an endocrine center. Surgery. 1996;120:948–952. [PubMed] 2. Chen H, Mack E, Starling JR. 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